Cyclic ureas useful as antiarrhythmic and antifibrillatory agents

ABSTRACT

Disclosed are cyclic urea-containing compounds that are useful as antiarrhythmic and/or antifibrillatory agents. These compounds have the following structure: ##STR1## where X and Y are each independently selected from various cyclic moieties; R 5  is a substituted or unsubstituted C 2  alkyl (thus providing a 6-membered cyclic urea); and R 1 , R 2 , R 3 , R 4 , L, and A are as defined in the specification. Also disclosed are compositions containing the compounds and methods of treating humans or other mammals afflicted with cardiac arrhythmias and/or cardiac fibrillation by administration of the compounds/compositions.

This is a division of application Ser. No. 08/479,256, filed on Jun. 7,1995, now U.S. Pat. No. 5,691,369.

BACKGROUND OF THE INVENTION

The present invention relates to novel cyclic urea compounds andpharmaceutical compounds thereof, useful in treating humans or othermammals with cardiac arrhythmia and/or cardiac fibrillation.

The novel cyclic urea compounds of the present invention are active asantifibrillatory and antiarrhythmic agents. The present compoundsexhibit broad efficacy against cardiac arrhythmia and fibrillation andcan be satisfactorily applied to substantially alleviate and/or preventarrhythmia and fibrillation. In addition, said compounds exhibit a lowerincidence of some of the undesirable side effects than do manyconventional antiarrhythmic therapies. An additional benefit of thecompounds described herein is that they exhibit both antifibrillatoryand antiarrhythmic activity; most conventional therapies generally donot exhibit efficacy as antifibrillatory agents. See, e.g. Coplen, S. E.et al., "Efficacy and Safety of Quinidine Therapy for Maintenance ofSinus Rhythm after Cardioversion: A meta-analysis," Circulation, Vol.82, pp. 1106-1116 (1990); and Echt, D. S. et al., "Mortality andMorbidity in Patients receiving Ecainide, Flecainide, or Placebo: TheCardiac Arrhythmia Suppression Trial", N. Engl. J. Med., Vol. 324, pp.781-788 (1991), both hereby incorporated by reference herein.

In a healthy, structurally sound heart, the precise, sequentialelectrical activation, then deactivation, of the entire cardiac musclethat occurs unerringly with each beat is characterized as normal cardiacrhythm. Arrhythmias are characterized as occurrences of abnormalelectrical activity that can interfere with normal cardiac rhythm. Theabnormal electrical activity can interfere with the initiation of,and/or the uniform spread of, the electrical wave (i.e. depolarizationfollowed by repolarization of the cardiac muscle) that triggers theheart to contract. The disruption of the smooth, cyclical process ofcardiac function associated with normal cardiac rhythm by the existenceof arrhythmias is, in some instances, life-threatening.

Arrhythmias range in severity from relatively benign (consisting ofasymptomatic and infrequent premature ventricular complexes [PVCs]) tolife-threatening (consisting of ventricular fibrillation, and sustainedventricular tachyarrhythmia). For an excellent review of arrhythmias andan overview of antiarrhythmic therapy, see, e.g. Bigger, Thomas J.,"Antiarrhythmic Treatment: An Overview", American Journal of Cardiology,Vol. 53, pp. 8B-16B, Feb. 27, 1984; Goldstein, S., "Toward a NewUnderstanding of the Mechanism and Prevention of Sudden Death inCoronary Heart Disease", Circulation, Vol. 82(1), pp. 284-88 (1990); andWoosley, R. L., "Antiarrhythmic Drugs", Annu. Rev. Pharmacol. Toxicol.,Vol. 31, pp. 427-455 (1991), all hereby incorporated by referenceherein. Life threatening arrhythmias are noted as a leading cause ofdeath worldwide. For instance, it is estimated that sudden cardiac deathresulting from ventricular fibrillation kills approximately400,000-600,000 people in the United States each year. U.S. Departmentof Health and Human Sciences (1985) NCHS Monthly Vital Statistics Report33:8-9.

Arrhythmias are generally classified into two types: 1) SupraventricularArrhythmias (for example, atrial fibrillation and flutter) and 2)Ventricular Arrhythmias (for example, ventricular tachyarrhythmia andventricular fibrillation and flutter).

Supraventricular arrhythmias are generally not life threatening.Individuals with these arrhythmias may experience a wide range ofsymptoms, from slight to severe intensity. These individuals may feelthe physical sensation of missed beats, extra beats, and/or flutter, mayoccasionally feel slightly light-headed or dizzy, and may have shortnessof breath and/or chest pain. Since this situation is, in fact, generallynot life threatening, more aggressive therapies such as conventionalantiarrhythmic drugs sometimes are not prescribed, because the sideeffects usually associated therewith may not be acceptable for anon-life-threatening condition. However, the novel compounds of thepresent invention are generally better tolerated than many of theconventional, currently available anti-arrhythmics; therefore, theywould likely be an acceptable therapy for individuals suffering fromsupraventricular arrhythmias and would substantially alleviate thediscomfort these individuals experience.

Ventricular arrhythmias, on the other hand, are potentially much moreserious and have been classified into three groups: 1) benign; 2)prognostically-significant (potentially lethal); and 3) life threatening(lethal). See, e.g. Morganroth, J. and Bigger, J. T., "Pharmacologicalmanagement of ventricular arrhythmias after the Cardiac ArrhythmiaSuppression Trial", Amer. J. Cardiol., Vol. 65, pp. 1497-1503 (1990),hereby incorporated by reference herein (hereinafter Morganroth &Bigger).

Individuals with benign arrhythmias exhibit very low risk of death,cardiac scarring, and heart disease. Benign ventricular arrhythmias arerelatively common and account for approximately 30% of all ventriculararrhythmias. Id. Benign arrhythmias, such as premature ventricularcomplexes (PVCs), pose minimal risks to individuals and rarely requireantiarrhythmic therapy. However, the PVCs may be of a frequency orcomplexity, or are associated with sufficiently alarming symptoms, sothat individuals experiencing them do not respond to reassurance thatthe arrhythmias and symptoms are not dangerous. They also may notrespond to most conventional treatment (e.g. beta-blockers). In thesecases, treatment with the novel compounds of the present invention willlikely be beneficial in these individuals.

Prognostically significant arrhythmias are associated with someadditional clinical presentation of cardiac disease, such as mild heartfailure, ischemic symptoms, and/or cardiac scarring. It has been statedthat approximately 65% of all ventricular arrhythmias are prognosticallysignificant. See, e.g., Morganroth & Bigger, at 1497.

Patients with life threatening arrhythmias may present with syncope(sudden loss of consciousness--usually fainting--associated withinsufficient brain perfusion), cardiac arrest, heart failure, and/ormyocardial ischemia, in the presence of structural heart disease. Lifethreatening arrhythmias are relatively uncommon; probably less than 10%of the individuals suffering from arrhythmias suffer from a lethal form.Morganroth & Bigger, p. 1497. However, due to the life-threateningnature of lethal ventricular arrhythmias and the severity of symptomsassociated therewith, they must be aggressively treated.

The novel compounds of the present invention are efficacious againstcardiac fibrillation and supraventricular or ventricular arrhythmias. Inaddition, the novel compounds of the present invention exhibit less ofmany of the undesirable side effects which have come to be tolerated intraditional antiarrhythmic therapy, for lack of acceptable alternatetherapies. For example, many current therapies cause pulmonary toxicity,cardiac depression, and neurologic effects, not specific to cardiactissue. For an excellent discussion of the side effects associated withconventional antiarrhythmic therapies see, e.g., Bigger, J. T. andHoffman, B. F., "Antiarrhythmic Drugs" in Goodman and Gilman's The Basisof Pharmacological Therapeutics, 8th edition, ed. A. G. Gilman, pp.840-873, New York: Pergamon; and Woosley, R. L., "AntiarrhythmicAgents", in The Heart, ed. J. W. Hurst, pp. 1682-1711, New York:McGraw-Hill (1990), both hereby incorporated by reference herein.

In addition, the novel compounds of the present invention are readilybioavailable. This feature facilitates treatment by oral administration,and therefore greatly facilitates patient compliance. In addition, thenovel compounds of the present invention are relatively inexpensive tomanufacture, and they exhibit a high degree of stability in oral dosageforms.

SUMMARY OF THE INVENTION

The novel cyclic ureas of the present invention, and theirpharmaceutically acceptable salts and estrs, are useful asantiarrhythmic and antifibrillatory agents and have the followinggeneral structure: ##STR2## wherein

(a) X is a saturated or unsaturated, 5-, 6-, or 7-membered heterocycleor carbocycle;

(b) R is selected from the group consisting of covalent bond, nil,heteroatom, carbonyl, heterocyclic ring, carbocyclic ring, alkyl,alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy, andacylamino;

(c) Y is a substituted or unsubstituted, saturated or unsaturated, 5-,6-, or 7-membered heterocyclic ring or carbocyclic ring, or is nil;

and wherein when R is nil, X and Y are fused ring systems; and when R isa covalent bond, X and Y are ring systems linked through a covalentbond; and when Y is nil, R is a covalent bond and X is bound to Lthrough R;

(d) R₁, R₂, and R₃ are independently selected from the group consistingof nil, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH, alkoxy, alkyl,alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acylamino, andacyloxy;

(e) L is selected from the group consisting of alkylamino, alkenylamino,alkylimino, alkenylimino, and acylamino; wherein the nitrogen atomthereof is bound to the nitrogen atom at the 1-position of the cyclicurea moiety;

(f) R₄ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkylacyl, and heteroalkyl;

(g) A is a substituted or unsubstituted, saturated or unsaturated,straight-chain or branched, C₁ -C₈ heteroalkyl, or a substituted orunsubstituted, saturated or unsaturated heterocycle having 5-, 6-, or7-members; and has one nitrogen atom which is adjacent to R_(4;) and

(h) R₅ is a substituted or unsubstituted C₁ or C₂ alkyl.

The Ring System (X-R-Y)

The novel cyclic urea compounds of the present invention are comprisedof a cyclic urea moiety connected to a ring system (X-R-Y) via a linkingmoiety (L). The cyclic ureas have a nitrogen atom at the 3-positionwhich is substituted with an amino-containing moiety (A) consisting ofan amino group separated from the nitrogen at the 3-position of thecyclic urea moiety by a spacing group (R₄). The moiety represented by(X-R-Y) is a ring system moiety and consists of one or more, preferablyone or two, fused or unfused, saturated or unsaturated, substituted orunsubstituted, carbocyclic rings or heterocyclic rings as definedherein. Each carbocyclic ring or heterocyclic ring contains 5, 6, or 7,preferably 5 or 6, members.

It is preferable that the ring system (X-R-Y) is polycyclic and iscomprised of two, unfused rings and even more preferable that the ringrepresented by Y which is adjacent to the linking moiety, L, be aheterocycle, most preferably a five-membered ring which contains anoxygen heteroatom at the 1-position. In addition, when there are tworings in the ring system, it is also preferable that the heterocycle Yis covalently bound to the ring at the 5-position of the heterocycle Yand at the 1-position of the ring X, and that the heterocycle Y is boundto the L moiety at the 2-position of the heterocycle Y.

Although not preferred, it is also possible for the ring system (X-R-Y)to consist of two rings (X and Y) which are separated by an alkyl,carbonyl, or a heteroatom, most preferably oxygen (R). In addition, thering system may be monocyclic; in this case, Y is nil and R is acovalent bond attached to L. However, when there is only one ring in thesystem, it is preferable that said ring be substituted with at leasttwo, and most preferably at least three, substituents chosen from thegroup consisting of, but not limited to, hydroxy, methyl, chloro,methoxy, and benzoyl.

When substituted, any or all of the members of the ring system (whethermonocyclic or polycyclic) may have one or more substituents, and may besubstituted with Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH,alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acylamino or acyloxy.

The Linking Moiety (L)

L is the linking moiety of the novel cyclic urea compounds of thepresent invention. The carbon-containing end of L is bound on to thering system, at Y, but if Y is nil, at X; most preferably at the2-position of the Y ring or at the 1-position of the X ring, if Y isnil. The nitrogen atom of the L moiety is bound to the nitrogen atom atthe 1-position of the cyclic urea moiety. The L moiety is selected fromthe group consisting of, but not limited to, alkylamino, alkenylamino,alkylimino, alkenylimino, and acylamino; L is preferably an alkylimino,most preferably a Cl alkylimino, CH═N.

The Cyclic Urea Moiety

The cyclic urea moiety of the novel compounds of the present inventiongives the novel compounds of the present invention their characteristicname. The cyclic urea moiety may be a 5- or 6-membered ring, preferablya 5-membered ring. The cyclic urea moiety is connected to the nitrogenatom of the linking moiety L at the nitrogen atom at the 1-position ofthe cyclic urea moiety. The cyclic urea moiety has the followingstructure: ##STR3## wherein R₅ is a C₁ or C₂ alkyl, preferably a C₁alkyl. A is a heteroalkyl or a heterocyclic ring and must always containat least one nitrogen atom which is attached to R₄. When A is aheteroalkyl, A may be straight-chained or branched, saturated orunsaturated, substituted or unsubstituted. When A is a heterocycle, A isa 5-, 6-, or 7-membered heterocyclic ring. Said ring may be substitutedor unsubstituted, preferably substituted, and saturated or unsaturated,preferably saturated. R₄ is connected to the nitrogen atom at the3-position of the cyclic urea moiety and to a nitrogen atom of A. R₄ isselected from the group consisting of, but not limited to alkyl,alkenyl, alkynyl, alkylacyl, and heteroalkyl.

When A is a substituted heteroalkyl, the substituents are selected fromthe group consisting of, but not limited to, methyl, hydroxyethyl,alkyl, aryl, heterocycle, arylalkyl, mercaptoethyl, and methanesulfonyl.

When heterocycle A has two heteroatoms and both are nitrogen, it ispreferable that the nitrogen atom not adjacent to R₄ be substituted withsubstituents selected from the group consisting of, but not limited to,methyl, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl,mercaptoethyl, and methanesulfonyl. When heterocycle A has only 1nitrogen atom, it is preferable that the heterocycle be substituted (atthe position para to the nitrogen connected to R₄ if the heterocycle Ahas 6-members) with substituents selected from the group consisting of,but not limited to, hydroxyethyl, hydroxy, oxo, and methyl.

Definitions and Usage of Terms

The following is a list of definitions for terms used herein.

"Heteroatom" is a nitrogen, sulfur, or oxygen atom. Groups containingone or more heteroatoms may contain different heteroatoms.

"Alkyl" is an unsubstituted or substituted, straight-chain or branched,saturated hydrocarbon chain having 1 to 8 carbon atoms, and preferably,unless otherwise stated, from 1 to 4 carbon atoms. Preferred alkylgroups include, but are not limited to, methyl, ethyl, propyl,isopropyl, and butyl.

"Heteroalkyl" is an unsubstituted or substituted, saturated chain havingfrom 3 to 8-members and comprising carbon atoms and one or twoheteroatoms.

"Alkenyl" is an unsubstituted or substituted, straight-chain orbranched, hydrocarbon chain having from 2 to 8 carbon atoms, preferablyfrom 2 to 4 carbon atoms, and having at least one olefinic double bond.

"Alkynyl" is an unsubstituted or substituted, straight-chain orbranched, hydrocarbon chain having from 2 to 8 carbon atoms, preferablyfrom 2 to 4 carbon atoms, and having at least one triple bond.

"Ring System" as used herein refers to the ring-containing moiety towhich the cyclic urea moiety is connected through the linking moiety, L.It is denoted herein by "X-R-Y" and may be a monocyclic ring moiety, ora fused, bridged, or spiro polycyclic ring moiety, and may containcarbocycles, heterocycles, or both. Monocyclic rings generally containfrom 3 to 8 atoms, preferably 5 to 7 atoms. Polycyclic ring systemsconsisting of two rings generally contain 6 to 16, preferably from 10 to12 atoms. Polycyclic ring systems consisting of three rings generallycontain 13 to 17 atoms, preferably 14 to 15 atoms.

"Carbocyclic ring" or "Carbocycle" as used herein is an unsubstituted orsubstituted, saturated, unsaturated or aromatic, hydrocarbon ring,generally containing from 3 to 8 atoms, preferably 5 to 7 atoms.

"Heterocyclic ring" or "Heterocycle" as used herein is an unsubstitutedor substituted, saturated or unsaturated or aromatic ring comprised ofcarbon atoms and one or more heteroatoms in the ring. Heterocyclic ringsgenerally contain from 3 to 8, preferably 5 to 7, atoms. Unlessotherwise stated, the heteroatom may be independently chosen fromnitrogen, sulfur, and oxygen.

"Aryl" is an aromatic carbocyclic ring. Preferred aryl groups include,but are not limited to, phenyl, tolyl, xylyl, cumenyl, and napththyl.

"Heteroaryl" is an aromatic heterocyclic ring. Preferred heteroarylgroups include, but are not limited to, thienyl, furyl, pyrrolyl,pyridinyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl, andtetrazolyl.

"Alkoxy" is an oxygen atom having a hydrocarbon chain substituent, wherethe hydrocarbon chain is an alkyl or alkenyl (e.g. --O-alkyl or--O-alkenyl). Preferred alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy, and alkyloxy.

"Hydroxyalkyl" is a substituted hydrocarbon chain which has a hydroxysubstituent (e.g. --OH), and may have other substituents. Preferredhydroxyalkyl groups include, but are not limited to, hydroxyethyl,hydroxypropyl, phenylhydroxyalkyl.

"Carboxyalkyl" is a substituted hydrocarbon chain which has a carboxysubstituent (e.g. --COOH), and may have other substituents. Preferredcarboxyalkyl groups include carboxymethyl, carboxyethyl, and their acidsand esters.

"Aminoalkyl" is a hydrocarbon chain (e.g. alkyl) substituted with anamine moiety (e.g. NH-alkyl-), such as dimethylamino alkyl.

"Alkylamino" is an amino moiety having one or two alkyl substituents(e.g. --N-alkyl).

"Alkenylamino" is an amino moiety having one or two alkenyl substituents(e.g. --N-alkenyl).

"Alkynylamino" is an amino moiety having one or two alkynyl substituents(e.g. --N-alkynyl).

"Alkylimino" is an imino moiety having one or two alkyl substituents(e.g. N═alkyl-).

"Arylalkyl" is an alkyl moiety substituted with an aryl group. Preferredarylalkyl groups include benzyl and phenylethyl.

"Arylamino" is an amine moiety substituted with an aryl group (e.g.--NH-aryl).

"Aryloxy" is an oxygen atom having an aryl substituent (e.g. --O-aryl).

"Acyl" or "carbonyl" is a moiety formed by removal of the hydroxy from acarboxylic acid (e.g. R--C(═O)--). Preferred alkylacyl groups include,but are not limited to, acetyl, propionyl, and butanol.

"Acyloxy" is an oxygen atom having an acyl substituent (e.g. --O-acyl);for example, --O--C(═O)-alkyl.

"Acylamino" is an amino moiety having an acyl substituent (e.g.--N-acyl); for example, --NH--(C═O)-alkyl.

"Halo", "halogen", or "halide" is a chloro, bromo, fluoro, or iodo atomradical. Chloro, bromo, and fluoro are preferred halides.

Also, as referred to herein, a "lower" hydrocarbon moiety (e.g., "lower"alkyl) is a hydrocarbon chain comprised of from, unless otherwisestated, 1 to 6, preferably from 1 to 4, carbon atoms.

A "pharmaceutically-acceptable" salt is a catonic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987, hereby incorporated by reference herein. Preferred catonicsalts include the alkali-metal salts (such as sodium and potassium), andalkaline earth metal salts (such as magnesium and calcium). Preferredanionic salts include the halides (such as chloride) salts.

A "biohydrolyzable ester" is an ester of the cyclic urea compounds thatdoes not interfere with the antiarrhythmic activity of the compounds, orthat is readily metabolized by a human or other mammal to yield anantiarrhythmically-active cyclic urea. Many such esters are known in theart, as described in World Patent Publication 87/05297, Johnston et al.,published Sep. 11, 1987, and hereby incorporated by reference herein.Such esters include lower alkyl esters, lower acyloxyalkyl esters (suchas acetoxylmethyl, acetoxyethyl, aminocarbonyl-oxymethyl,pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (suchas phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkylesters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl andisopropoxycarbonyloxyethyl esters), alkoxyalkylesters, choline esters,and acylamino alkyl esters (such as acetamidomethyl esters).

As defined above and as used herein, substituent groups may themselvesbe substituted. Such substitution may be with one or more substituents.Such substituents include, but are not limited to, those listed in C.Hansch and A. Leo, Substituent Constants for Correlation Analysis inChemistry and Biology (1979), hereby incorporated by reference herein.Preferred substituents include, but are not limited to, alkyl, alkenyl,alkoxy, hydroxy, oxo, amino, aminoalkyl (e.g. aminomethyl, etc.), cyano,halo, carboxy, alkoxyacetyl (e.g. carboethoxy, etc.), thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl,piperazinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo,hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention encompasses certain novel cyclic ureas, methodsfor their manufacture, pharmaceutical compositions thereof, and a methodof treatment utilizing said novel compounds and pharmaceuticalcompositions thereof for cardiac arrhythmias and/or cardiac fibrillationin humans or other mammals. Specific compounds and compositions to beused in the invention must, accordingly, be pharmaceutically-acceptable.As used herein, such a "pharmaceutically-acceptable" component is onethat is suitable for use with humans and/or other mammals without undueadverse side effects (such as toxicity, irritation, and allergicresponse), commensurate with a reasonable benefit/risk ratio.

Novel Cyclic Urea Compounds

The compounds of this invention, herein referred to as "cyclic ureas",encompass any of a variety of cyclic urea compounds having the followinggeneral structure: ##STR4## wherein

(a) X is a saturated or unsaturated, 5-, 6-, or 7-membered heterocycleor carbocycle;

(b) R is selected from the group consisting of covalent bond, nil,heteroatom, carboxyl, heterocyclic ring, carbocyclic ring, alkyl,alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy, andacylamino;

(c) Y is a substituted or unsubstituted, saturated or unsaturated, 5-,6-, or 7-membered heterocycle or carbocycle; or is nil;

and wherein when R is nil, X and Y are fused ring systems; and when R isa covalent bond, X and Y are ring systems linked through a covalentbond; and when Y is nil, R is a covalent bond and X is bound to Lthrough R;

(d) R₁, R₂, and R₃ are independently selected from the group consistingof nil, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, SO₂ NH₂, COOH,alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acylamino and acyloxy;

(e) L is selected from the group consisting of alkylamino, alkenylamino,alkylimino, alkenylimino, and acylamino; wherein the nitrogen atom of Lis bound to the nitrogen atom at the 1-position of the cyclic urea ringmoiety;

(f) R₄ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkylacyl and heteroalkyl;

(g) A is a substituted or unsubstituted, saturated or unsaturated,straight-chain or branched C₁ -C₈ heteroalkyl or a substituted orunsubstituted, saturated or unsaturated heterocycle having 5-, 6-, or7-members; and has at least one nitrogen atom which is adjacent to R₄,and

(h) R₅ is a substituted or unsubstituted C₁ or C₂ alkyl;

and the pharmaceutically-acceptable salts and esters thereof.

The Ring System (X-R-Y)

The novel cyclic urea compounds of the present invention are comprisedof a cyclic urea moiety connected to a ring system (X-R-Y) via a linkingmoiety (L). The cyclic ureas have a nitrogen atom at the 1-position andalso at the 3-position. The nitrogen atom at the 3-position issubstituted with an amino-containing group (A) separated from the,nitrogen atom at the 3-position of the cyclic urea moiety by a spacinggroup (R₄).

The ring system (X-R-Y) is a ring-containing moiety and consists of oneor more, preferably one or two, fused or unfused, saturated orunsaturated, substituted or unsubstituted, rings as defined herein.Accordingly, the ring system may be monocyclic (Y is nil) or polycyclic(both X and Y are rings or all of X, R, and Y are rings). Each ring maybe either a carbocycle or a heterocycle, and may contain 5, 6, or 7,preferably 5 or 6, members.

It is preferable that the ring system is polycyclic and is comprised oftwo, unfused rings. It is more preferable that the ring (Y) adjacent tothe linking moiety (L) is a heterocycle, most preferably a five-memberedring which contains an oxygen atom at the 1-position. In addition, whenthere are two rings in the ring system, it is preferable that theheterocycle (Y) is covalently bound (through R) to the other ring (X) atthe 5-position of the heterocycle Y and at the 1-position of ring X, andthat heterocycle Y is bound to the carbon-containing end of the L moietyat the 2-position of the heterocycle.

Although not preferred, it is acceptable for the ring system to be apolycyclic ring system comprised of two rings (X and Y) which areseparated by an alkyl, a carbonyl, or a heteroatom, preferably oxygen(R). In addition, a suitable ring system might include a polycyclic ringsystem comprised of two rings (X and Y) which are fused (R is nil) orthree rings (X, R, and Y) which are fused. When R is a ring, it ispreferably a 5- or 6-membered carbocycle or heterocycle.

A particularly suitable ring system is monocyclic, therefore, consistingof only one ring (X) which is covalently bound to the carbon-containingportion of L (R is a covalent bond and Y is nil). However, when there isonly one ring in the ring system, it is preferable that the ring is a6-membered carbocycle, which is more preferably substituted with atleast two, and most preferably with at least three, substituentsindependently chosen from the group consisting of, but not limited to,hydroxy, methyl, chloro, methoxy, and benzoyl.

When substituted, any or all of the members of the ring system, whethermonocyclic or polycyclic, may have one or more substituents. Saidsubstituents may be independently selected from the group consisting of,and not limited to, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH,alkoxyl, alkoxycarbonyl, hydroxyalkyl, alkyl, aminoalkyl, acylamino,acyloxy, and carboxyalkyl, especially Cl, F, Br, OH and CH₃.

Preferred ring systems of the novel cyclic ureas include, but are notlimited, for example, to monocyclic rings including, but not limited to,2-acetoxy-5-chlorophenyl;3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl; 2-thienyl;4-pyrimidinyl; 5-methoxycarbonyl-2-furanyl; cyclohexyl;5-chloro-2-hydroxyphenyl; 5-chloro-2-methoxyphenyl;2-methanesulfonylaminophenyl; 3-aminophenyl; 2-methoxyphenyl;5-ethyl-2-furanyl; 3-methoxyphenyl; 2-aminophenyl; 2-furanyl;3,5-dimethyl-4-hydroxyphenyl; and 5-acetyloxymethyl-2-furanyl. Suitablepolycyclic ring systems which consist of two unfused rings, covalentlybound to one another include, for example, but are not limited to,5-(4-carboxyphenyl)-2-furanyl; 5-(4-methanesulfonylphenyl)-2-furanyl;5-(3,4-dimethoxyphenyl)-2-furanyl;5-(4-methanesulfonylaminophenyl)-2-furanyl;5-(4-bromophenyl)-2-oxazolyl; S-(4-methoxyphenyl)-2-furanyl;5-(1-cyclohexen-1-yl)-2-furanyl; 5-cyclohexyl-2-furanyl;5-(3-trifluoromethylphenyl)-2-furanyl; 5-(4-methylphenyl)-2-furanyl;2-(4-chlorophenyl)-3-furanyl; 5-(4-chlorophenyl)-2-furanyl;5-(4-fluorophenyl)-2-furanyl. Suitable polycyclic ring systems whichconsists of two unfused rings each connected to one another via aheteroatom, alkyl, or other non-cyclic carbon-containing group include,for example, but are not limited to, 2-benzyloxy-5-chlorophenyl;4-benzyloxyphenyl; 3-(4-t-butylphenyloxy)phenyl;3-benzoyl-2,4-dichlorophenyl; 2-chloro-3-benzyloxyphenyl;3-(4-chlorophenoxyl) phenyl. Suitable polycyclic ring systems containingtwo or more fused rings include, for example, but are not limited to,1H-indol-3-yl; 2-fluorenyl; 2-naphthyl; 2-hydroxy-1-naphthyl;2-quinolinyl; 5-chloro-2-benzofuranyl.

Preferred ring systems (X-R-Y) of the novel cyclic ureas defined hereininclude, but are not limited to: ##STR5## The Linking Moiety (L)

L is the linking moiety of the novel cyclic urea compounds of thepresent invention. The carbon-containing end of L is bound to the X-R-Yring system at Y, but if Y is nil, at X; most preferably at the2-position of the Y ring, or at the 1-position of X, if Y is nil. Thenitrogen atom of the L moiety is bound to the nitrogen atom at the1-position of the cyclic urea moiety. The L moiety is selected from thegroup consisting of alkylamino, alkenylamino, alkylimino, alkenylimino,and acylamino, preferably alkylimino, most preferably a C₁ alkylimino,CH═N.

The Cyclic Urea Moiety

The cyclic urea moiety of the novel compounds of the present inventiongives the novel compounds of the present invention their characteristicname. The cyclic urea moiety may be a 5- or 6-membered ring, preferablya 5-membered ring. The cyclic urea moiety has the following structure:##STR6## wherein R₅ is a C₁ or C₂ alkyl, preferably a C₁ alkyl. When R₅is a C₁ alkyl, the cyclic urea is a 5-membered ring and when R₅ is a C₂alkyl, the cyclic urea is a 6-membered ring.

A is a straight chain or branched, substituted or unsubstituted,saturated or unsaturated C₁ -C₈ heteroalkyl or a substituted orunsubstituted, saturated or unsaturated 5-, 6-, or 7-, preferably 5- or6-, membered heterocyclic ring. The A moiety, whether a heteroalkyl or aheterocycle, must have at least one nitrogen atom which must be bound toR₄.

When A is a substituted heteroalkyl, the substituents are selected fromthe group consisting of, but not limited to, methyl, hydroxyethyl,alkyl, aryl, heterocycle, arylalkyl, mercaptoethyl, and methanesulfonyl.

When A has two nitrogen atoms, it is preferable that the nitrogen atomnot adjacent to R₄ (which in the case of a 6-membered heterocycle ispara to the nitrogen atom adjacent to R₄) is substituted withsubstituents selected from the group consisting of, but not limited to,methyl, hydroxyethyl, alkyl, aryl, mercaptoethyl, methanesulfonyl,heterocycle, and arylalkyl. When heterocycle A has only one nitrogenatom, and A is a 6-membered ring, the position para to the nitrogen atomwhich is adjacent to R₄ is preferably substituted with substituentsselected from the group consisting of, but not limited to, hydroxyethyl,hydroxy, oxo, and methyl.

Suitable A moieties, accordingly, may include, but are not limited to,the following: Moieties where A is a heteroalkyl include, but are notlimited to, dimethylamino; diethylamino; bis-2-hydroxyethylamino;bis-[(1-methyl)ethyl]amino; N-benzyl-N-methylamino;N-(2-hydroxyethyl)-N-methylamino. Suitable A moieties where A is aheterocycle include, but are not limited toN-[(1-methyl)ethyl]--N-[2-hydroxy-2-[(4-methanesulfonylamino)phenyl]ethyl]amino; 4-phenyl-1-piperazinyl;4-(2-hydroxyethyl)-1-piperazinyl; 4-[(1-methyl)ethyl]-1-piperazinyl;4-[(2-methyl)propyl]-1-piperazinyl; 4-hexyl-1-piperazinyl;4-benzyl-1-piperazinyl; 1-piperazinyl; 4-hydroxy-1-piperidinyl;4-methyl-1-piperazinyl; 4-n-butyl-1-piperazinyl; 4-ethyl-1-piperazinyl;3-(4-methyl-1-piperazinyl)-3-oxopropyl; 4-phenyl-1-piperazinyl;N-(2-pyridinyl)-1-piperazinyl; N-(2-pyrimidinyl)-1-piperazinyl;4-(4-methoxyphenyl)-1-piperazinyl; 4-acetyl-1-piperazinyl;N-methyl-N-phenylamino; 1-imidazolyl; 4-(2-methylphenyl)-1-piperazinyl;4-(4-methanesulfonylaminophenyl)-1-piperazinyl; N-morpholinyl;N-thiomorpholinyl; 4-oxo-1-piperidinyl;2-(t-butoxycarbonyl)-1-pyrrolidinyl; pyrrolidinyl;4-(4-acetylphenyl)-1-piperazinyl; hexahydro-1H-azepin-1-yl.

Preferred amine-containing (A) moieties of the novel cyclic ureasdefined herein include, but are not limited to: ##STR7##

R₄ is connected to the nitrogen atom at the 3-position of the cyclicurea moiety and to a nitrogen atom of A. R₄ is selected from the groupconsisting of, and not limited to alkyl, alkenyl, alkynyl, alkylacyl,and heteroalkyl, especially C₃ -C₆ alkyl, i.e. propyl, butyl, pentyl,and hexyl.

As stated hereinabove, the novel cyclic urea compounds of the presentinvention are comprised of a cyclic urea moiety connected to a ringsystem via a linking moiety. Accordingly, suitable compounds of thepresent invention include, but are not limited to, the followingcompounds, and the pharmaceutically-acceptable esters and salts thereof,especially the maleate and hydrochloride salts:1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone;1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)-butyl]-2-imidazolidinone;1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl )butyl ]-2-imidazolidinone;1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[2-(dimethylamino)ethyl]-2-imidazolidinone;1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone;1-[[5-chloro-2-benzofuranyl)methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone;1-[[3-benzoyl-2,4-dichlorophenyl)methylene]amino]-3-[3-dimethylamino)propyl]-2-imidazolidinone;1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]tetrahydro-2-(1H)pyrimidinone;1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-[4-(2-hydroxyethyl)-1-piperazinyl]butyl]-2-imidazolidinone;1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(4-methyl-1-piperazinyl)propyl]-2-imidazolidinone;1-[[cyclohexyl)methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone.

Examples A-D herein illustrate how to make preferred novel cyclic ureacompounds described herein.

Pharmaceutical Compositions Containing Novel Cyclic Urea Compounds

The novel cyclic urea compounds of the present invention may beadministered to humans or other mammals by a variety of routes,including, but not limited to, oral dosage forms, and injections(intravenous, intramuscular, subcutaneous and intraperitoneal). Numerousother dosage forms containing the novel cyclic urea compounds of thepresent invention can be readily formulated by one skilled in the artutilizing the suitable pharmaceutical excipients as defined below. Forconsiderations of patient compliance, oral dosage forms are generallymost preferred.

The term "pharmaceutical composition" as used herein means a combinationcomprised of a safe and effective amount of the cyclic urea compoundactive ingredient, or mixture thereof, and pharmaceutically-acceptableexcipients.

The phrase "safe and effective amount", as used herein, means an amountof a compound or composition large enough to significantly positivelymodify the symptoms and/or condition to be treated, but small enough toavoid serious side effects (at a reasonable benefit/risk ratio), withinthe scope of sound medical judgment. The safe and effective amount ofactive ingredient for use in the pharmaceutical compositions to be usedin the method of the invention herein will vary with the particularcondition being treated, the age and physical condition of the patientbeing treated, the severity of the condition, the duration of thetreatment, the nature of concurrent therapy, the particular activeingredient being employed, the particular pharmaceutically-acceptableexcipients utilized, and like factors within the knowledge and expertiseof the attending physician.

The term "pharmaceutically-acceptable excipients" as used hereinincludes any physiologically inert, pharmacologically inactive materialknown to one skilled in the art, which is compatible with the physicaland chemical characteristics of the particular cyclic urea compoundactive ingredient selected for use. Pharmaceutically-acceptableexcipients include, but are not limited to, polymers, resins,plasticizers, fillers, binders, lubricants, glidants, disintegrants,solvents, co-solvents, buffer systems, surfactants, preservatives,sweetening agents, flavoring agents, pharmaceutical grade dyes orpigments, and viscosity agents.

The term "oral dosage form" as used herein means any pharmaceuticalcomposition intended to be systemically administered to an individual bydelivering said composition to the gastrointestinal tract of anindividual, via the mouth of said individual. For purposes of thepresent invention, the delivered form can be in the form of a tablet,coated or non-coated; solution; suspension; or a capsule, coated ornon-coated.

The term "injection" as used herein means any pharmaceutical compositionintended to be systemically administered to a human or other mammal, viadelivery of a solution or emulsion containing the active ingredient, bypuncturing the skin of said individual, in order to deliver saidsolution or emulsion to the circulatory system of the individual, eitherby intravenous, intramuscular, subcutaneous or intraperitonealinjection.

The rate of systemic delivery can be satisfactorily controlled by oneskilled in the art, by manipulating any one or more of the following:

(a) the active ingredient proper;

(b) the pharmaceutically-acceptable excipients; so long as the variantsdo not interfere with the activity of the particular active ingredientselected;

(c) the type of the excipient, and the concomitant desirable thicknessand permeability (swelling properties) of said excipient;

(d) the time-dependent conditions of the excipient itself and/or withinthe excipients;

(e) the particle size of the granulated active ingredient; and

(f) the pH-dependent conditions of the excipients.

In particular, the solubility, acidity, and susceptibility to hydrolysisof the different cyclic urea active ingredients, such as acid additionsalts, salts formed with the carboxylic group, e.g., alkali metal salts,alkaline earth metal salts, etc., and esters, e.g., alkyl, alkenyl,aryl, aralkyl, may be used as guidelines for the proper choice. Inaddition, suitable pH-conditions might be established within the oraldosage forms by adding a suitable buffer to the active ingredient inaccordance with the desired release pattern.

As stated hereinabove, pharmaceutically acceptable excipients include,but are not limited to, resins, fillers, binders, lubricants, solvents,glidants, disintegrants cosolvents, surfactants, preservatives,sweetener agents, flavoring agents, buffer systems, pharmaceutical-gradedyes or pigments, and viscosity agents.

The preferred solvent is water.

Flavoring agents among those useful herein include those described inRemington's Pharmaceutical Sciences, 18th Edition, Mack PublishingCompany, 1990, pp. 1288-1300, incorporated by reference herein. Thepharmaceutical compositions suitable for use herein generally containfrom 0-27% flavoring agents.

Dyes or pigments among those useful herein include those described inHandbook of Pharmaceutical Excipients, pp. 81-90, 1986 by the AmericanPharmaceutical Association & the Pharmaceutical Society of GreatBritain, incorporated by reference herein. The pharmaceuticalcompositions described herein generally contain from 0-2% dyes orpigments.

Preferred co-solvents include, but are not limited to, ethanol,glycerin, propylene glycol, polyethylene glycols. The pharmaceuticalcompositions of the present invention include from 0-50% co-solvents.

Preferred buffer systems include, but are not limited to, acetic, boric,carbonic, phosphoric, succinic, malaic, tartaric, citric, acetic,benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids andtheir sodium, potassium and ammonium salts. Particularly preferred arephosphoric, tartaric, citric, and acetic acids and salts. Thepharmaceutical compositions of the present invention generally containfrom 0-5% buffer systems.

Preferred surfactants include, but are not limited to, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrosemonoesters and lanolin esters and ethers, alkyl sulfate salts, sodium,potassium, and ammonium salts of fatty acids. The pharmaceuticalcompositions of the present invention include 0-2% surfactants.

Preferred preservatives include, but are not limited to, phenol, alkylesters of parahydroxybenzoic acid, o-phenylphenol, benzoic acid and thesalts thereof, boric acid and the salts thereof, sorbic acid and thesalts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuricacetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridiniumchloride, methyl paraben, and propyl paraben. Particularly preferred arethe salts of benzoic acid, cetylpyridinium chloride, methyl paraben andpropyl paraben. The compositions of the present invention generallyinclude from 0-2% preservatives.

Preferred sweeteners include, but are not limited to, sucrose, glucose,saccharin, sorbitol, mannitol, and aspartame. Particularly preferred aresucrose and saccharin. Pharmaceutical compositions of the presentinvention include 0-5% sweeteners.

Preferred viscosity agents include, but are not limited to,methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate,carbomer, povidone, acacia, guar gum, xanthan gum and tragacanth.Particularly preferred are methylcellulose, carbomer, xanthan gum, guargum, povidone, sodium carboxymethylcellulose, and magnesium aluminumsilicate. Compositions of the present invention include 0-5% viscosityagents.

Preferred fillers include, but are not limited to, lactose, mannitol,sorbitol, tribasic calcium phosphate, dibasic calcium phosphate,compressible sugar, starch, calcium sulfate, dextro and microcrystallinecellulose. The compositions of the present invention contain from 0-75%fillers.

Preferred lubricants include, but are not limited to, magnesiumstearate, stearic acid, and talc. The pharmaceutical compositions of thepresent invention include 0.5-2% lubricants.

Preferred glidants include, but are not limited to, talc and colloidalsilicon dioxide. The compositions of the present invention include from1-5% glidants.

Preferred disintegrants include, but are not limited to, starch, sodiumstarch glycolate, crospovidone, croscarmelose sodium, andmicrocrystalline cellulose. The pharmaceutical compositions of thepresent invention include from 4-15% disintegrants.

Preferred binders include, but are not limited to, acacia, tragacanth,hydroxypropylcellulose, pregelatinized starch, gelatin, povidone,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,sugar solutions, such as sucrose and sorbitol, and ethylcellulose. Thecompositions of the present invention include 1-10% binders.

Accordingly, the pharmaceutical compositions of the present inventioninclude from 15-95% of a cyclic urea compound active ingredient, ormixtures thereof; 0-2% flavoring agents; 0-50% co-solvents; 0-5% buffersystem; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5%viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15%disintegrants; and 1-10% binders.

Suitable pharmaceutical compositions are described herein in ExamplesE-J. It is well within the capabilities of one skilled in the art tovary the non-limiting examples described herein to achieve a broad rangeof pharmaceutical compositions.

Method of Treating Arrhythmias with the Novel Cyclic Urea Compounds

The novel compounds of the present invention are efficacious in treatinghumans or other mammals afflicted with supraventricular arrhythmias andventricular arrhythmias, and/or cardiac fibrillation. As statedhereinabove, except in rare cases, supraventricular arrhythmias are notdeemed to be life threatening and are generally not aggressively treatedwith conventional antiarrhythmic drugs due to their undesirable sideeffects. Accordingly, this type of arrhythmia is usually notaggressively treated to merely relieve symptoms which are characterizedas mild to severe. However, the novel compounds of the present inventionare generally well tolerated and generally exhibit less of theundesirable side effects than many conventional antiarrhythmic drugsand, accordingly, may well be an acceptable therapy to alleviate thephysical and emotional symptoms suffered by individuals exhibitingsupraventricular arrhythmias who are, in fact, experiencing discomfort,even though not in a life-threatening situation.

As stated hereinabove, the novel cyclic urea compounds of the presentinvention are also effective in treating ventricular arrhythmias, whichare, as a rule, much more serious than atrial arrhythmias and,accordingly, require aggressive therapy. Because of the potentialseriousness of some ventricular arrhythmias, many patient-typeclassifications have arisen.

Individuals suffering from benign ventricular arrhythmias are, from aphilosophical standpoint of whether-to-treat, similar to thoseindividuals experiencing supraventricular arrhythmias. These individualsdo not have heart disease and may experience syncope, dizziness, andpalpitations, and often suffer from a certain amount of emotionaldistress stemming from uncertainty caused by their physical symptoms.These individuals generally suffer from PVCs which are, for the mostpart, physically harmless, but understandably give rise to some degreeof anxiety. The novel cyclic urea compounds of the present inventiongenerally exhibit less of the undesirable side effects which may havemade the use of many conventional antiarrhythmic therapies, heretoforereserved for more serious and/or life-threatening disease states,undesirable. However, these individuals would likely benefit fromtherapy which is generally better tolerated.

Another class of individuals who may benefit from therapy utilizing thenovel cyclic urea compounds of the present invention are thoseindividuals who are characterized as having "prognostically-significant"arrhythmias. These individuals generally have suffered a myocardialinfarction and may have PVCs and/or episodes of non-stained ventriculartachyarrhythmia, either symptomatic and asymptomatic. They do notexhibit the same degree of immediate, urgent life-threatening symptomsas do those individuals described hereinabelow, and are not, byconventional characterization, in danger of immediate- or near-death.They are, however, at a significantly greater risk of sudden death thanthe general populace, and, accordingly, would be at a lessened risk ofcardiac failure with therapy from the novel compounds of the presentinvention. See Morganroth & Bigger at 1498.

Other individuals exist who continually exhibit life-threateningarrhythmias and are in danger of immediate-or-near death. In theseindividuals, there is generally exhibited sustained ventriculartachyarrhythmia or ventricular fibrillation. The ventricular arrhythmiasin these individuals generally produce hemodynamically significant signsor symptoms such as syncope, heart failure, myocardial ischemia orhypotension. These patients have the highest risk of sudden cardiacdeath and usually the most severe form of underlying cardiac disease.See Morganroth & Bigger at p. 1498. The novel compounds of the presentinvention are effective, aggressive antiarrhythmic therapy suitable foruse in this class of individuals, but with less of some of theundesirable side effects generally heretofore tolerated withconventional antiarrhythmic drugs, out of necessity and theunavailability of a suitable alternative to treat the life-threateningarrhythmias.

As stated above, the novel antiarrhythmic agents of the presentinvention exhibit less of many of the undesirable side effectsassociated with many conventional antiarrhythmic therapies. These sideeffects include, but are not limited to, pulmonary toxicity, cardiacdepression, and neurological effects nonspecific to the cardiac tissue.

In addition, the novel compounds of the present invention areantifibrillatory as well as antiarrhythmic; they prevent sudden cardiacdeath by uniformly prolonging the unexcitable period of the heart duringeach heartbeat. Conventional therapies exhibit anesthetic and/or cardiacdepressive properties which merely make the heart less responsive, notless fibrillatory.

Accordingly, the novel cyclic urea compounds of the present inventionare useful in treating cardiac arrhythmias and/or cardiac fibrillationin humans or other mammals. Therefore, the present invention relates toa method for treating a human or other mammal suffering from cardiacarrhythmia and/or cardiac fibrillation which comprises administering tosaid human or other mammal a safe and effective amount of apharmaceutical composition comprising from 15-90% of a cyclic ureacompound active ingredient, or mixtures thereof, and from 10-85%pharmaceutically-acceptable excipients.

The Examples K-R herein exhibit certain patient situations andillustrate the methods in which pharmaceutical compositions containingthe novel cyclic urea compounds of the present invention may be used totreat cardiac arrhythmias and/or fibrillation. It is well within thecapabilities of one skilled in the art to vary the non-limiting examplesdescribed herein to treat a broad class of individuals suffering fromcardiac arrhythmia and/or fibrillation.

The following examples will further serve to illustrate the presentinvention.

EXAMPLE A Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinoneHydrochloride ##STR8##

1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinonehydrochloride is prepared as described hereinbelow.

I. Synthesis of Dimethylaminopropyl Chloride

Dimethylaminopropyl chloride is prepared by neutralizing thehydrochloride salt with aqueous NaOH in H₂ O. The neutralized solutionis extracted with ether. The ether extract is dried over MgSO₄, filteredand concentrated under reduced pressure on a rotary evaporator to aliquid residue.

II. Synthesis of 1-[(Phenylmethylene)amino]-2-imidazolidinone

A stirring solution of 65 g (0.75 mole) of 2-imidazolidinone in 2000 mlof 2 N H₂ SO₄ is cooled to SAC. A 53 g (0.77 mole) portion of NaNO₂ isadded portionwise, over a 15 minute period, maintaining the temperatureat 0° C. The resulting mixture is stirred at 0° C. for 2 hours. A 108 g(1.65 mole) portion of zinc dust is added portionwise, over a 1 hourperiod, maintaining the temperature at 0° C. The reaction is stirred at0° C. for 0.5 hour and then at ambient temperature for 1 hour. Theexcess zinc is removed by filtration. The filtrate is treated all atonce, with a solution of 80 g (0.75 mole) of benzaldehyde, in 400 ml ofS.D.A. #32 and the resulting mixture is stirred for 16 to 18 hours atambient temperature. The solid is collected by filtration, washed withH₂ O, and air-dried to yield 124 g (87%) of1-[(phenylmethylene)amino]-2-imidazolidinone.

III. Synthesis of 3-[3-(Dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone

A near solution of 9.46 g (0.050 mole) of 1-[(phenylmethylene)amino]-2-imidazolidinone in 125 ml of dimethylformamide istreated portionwise with 2.0 g (0.050 mole) of NaH (60% dispersion inmineral oil) with the temperature rising to 30° C. The reaction isstirred at ambient temperature for 15 minutes with a solid forming. A100 ml portion of dimethylformamide is added, to aid in stirring, andthe mixture is stirred at 80° to 90° C. for 30 minutes. The mixture iscooled to ambient temperature and treated all at once with 12.2 g (0.100mole) of dimethylaminopropyl chloride (prepared as described in Part Iabove). The resulting mixture is heated at 80° to 90° C. for 3 hourswith near dissolution. The solvent is removed in vacuo. The residualsemi-solid is dissolved in H₂ O (150 ml), and extracted with ethylacetate (2×200 ml). The combined extracts are dried over MgSO₄ and thesolvent is removed in vacuo. The residual solid is washed with ether andair-dried to yield 4.8 g of3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone.

IV. Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)proyl]-2-imidazolidinonehydrochloride

A solution of 4.8 g (0.017 mole) of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone (prepared asdescribed in Part III above) in 125 ml of 2 N HCl is treated with 1 g of5% Pd/C (50% H₂₀) and placed on the Parr reduction apparatus, with thetheoretical amount of H₂ being absorbed over a 30 minute period. Thecatalyst is removed by filtration and the solvent is removed in vacuo.The residual oil is dissolved in 100 ml of dimethylformamide and treatedall at once with 3.51 g (0.0170 mole) of5-(4-chlorophenyl)-2-furancarboxaldehyde (prepared as described in U.S.Pat. No. 4,882,354 to Huang et al., (issued Nov. 21, 1989), assigned toNorwich Eaton Pharmaceuticals, Inc., see Example 3, cols. 7 & 8, herebyincorporated by reference herein) with dissolution. A 1.0 g portion of 3Angstrom molecular sieves is added and the reaction is stirred 16 to 18hours at ambient temperature. The resulting mixture is heated to refluxwith dimethylformamide being added to dissolution. The molecular sievesare removed by filtration and the solvent is removed in vacuo. Theresidual semi-solid is crystallized by trituration with ether. The solidis recrystallized from S.D.A. #32, (activated charcoal) and dried in avacuum pistol over refluxing ethyl acetate to yield 2.7 g of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(3-dimethylaminopropyl)-2-imidazolidinonehydrochloride.

EXAMPLE B Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinoneDimaleate ##STR9##

1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidolidinonedimaleate is prepared as described hereinbelow.

I. Synthesis of1-Phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone

A stirred mixture of 1-phenylmethylenamino-2-imidazolidinone (27.6 g,0.1458 mole) [prepared as in Example A, Part II] in dimethylformamide(500 ml) is treated portionwise with 60% NaH in mineral oil (5.8 g,0.1458 mole) over 30 minutes. The resulting mixture is stirred atambient temperature 30 minutes, then heated at 80-90° C. for 30 minutes.The resulting thick mixture is cooled to ambient temperature, and1-bromo-4-chlorobutane (50.0 g, 0.2916 mole, 2 eq) is added in oneportion. The mixture is heated at 80°-90° C. After 30 minutes, anear-solution is formed followed, by gradual precipitation of a smallamount of solid. The mixture is heated at 80°-90° C. temperature for 3hours, then stirred at ambient temperature for 18 hours. The mixture isfiltered (celite) removing a small amount of insoluble material. Thefiltrate is concentrated under reduced pressure to an oily residue. Thisresidue is triturated with H₂ O giving a solid. The solid is collectedand air-dried. This solid is triturated by stirring in anhydrous ether(350 ml) for one hour. The solid is collected and air-dried to give 36.4g (0.130 mole) of1-phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone.

II. Synthesis of1-Phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone

A stirred mixture of1-phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone (36.4 g,0.1301 mole), acetone (700 ml) and sodium iodide (42.9 g, 0.2862 mole)is heated to reflux which is maintained for 24 hours. The mixture isfiltered hot, removing the solid. After cooling, the filtrate is pouredinto H₂ O (2000 ml) and stirred 1 hour. The solid is collected, washedwith H₂ O, and air-dried to give 31.4 g, (0.0845 mole) of1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone.

III. Synthesis of1-Phenylmethyleneamino-3-f4-[4-methyl-1-piperazinyl)butyl]-2-imidazolidinone

A stirred solution of1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone (10.0 g, 0.0269mole), dimethylformamide (150 ml) and 1-methylpiperazine (6.0 ml, 3.4 g,0.0539 mole) is heated to reflux. Reflux is maintained for 2.5 hours.The solution is concentrated under reduced pressure to a semi-solidresidue. This residue is dissolved in CHCl₃ (300 ml), then washed withsaturated NaHCO₃ solution. (3×400 ml), H₂ O (2×100 ml) and dried overMgSO₄. The filtered solution is concentrated under reduced pressure toan oily residue. This residue is triturated in hexane (300 ml) bystirring. The solid is collected and air-dried to give 8.0 g (0.0233mole) of1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinone.

IV. Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinoneDimaleate Salt

A mixture of1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinone(3.0 g, 0.0087 mole), 2 N HCl (125 ml) and 5% Pd/C (50% H₂ O) (2.0 g) issubjected to hydrogen on a Parr apparatus at 40 psi at ambienttemperature. After 3 hours, 100% of the theoretical H₂ uptake isobserved. The filtrate is concentrated under reduced pressure to an oilyresidue. This residue is azeotroped with absolute ethanol (1×25 ml),then concentrated under high vacuum to an oily residue.

A solution of the above residue, dimethylformamide (50 ml) and5-(4-chlorophenyl)-2-furancarboxaldehyde (prepared as described in U.S.Pat. No. 4,882,354 to Huang et al., assigned to Norwich EatonPharmaceuticals, Inc., issued Nov. 21, 1989, see Example 3, cols. 7, 8hereby incorporated by reference herein) (1.80 g, 0.0087 mole) isstirred at ambient temperature for 17-18 hours. The mixture isconcentrated under reduced pressure to a solid residue. This residue issuspended in H₂ O (250 ml) then extracted with ethyl acetate (4×75 ml).The aqueous phase is made basic with saturated NaHCO₃ solution. Thiscloudy mixture is extracted with ethyl acetate (3×100 ml). The extractis washed with H₂ O (2×50 ml) then dried over MgSO₄ (activatedcharcoal). The filtered solution is concentrated under reduced pressureto a solid residue (1.28 g, 0.0028 mole). This residue is dissolved inabsolute ethanol (50 ml), then treated with a solution of maleic acid(0.673 g, 0.0058 mole) dissolved in absolute ethanol (5 ml). Theresulting mixture is stirred at ambient temperature for 1 hour. Thesolid is collected and air-dried. Further drying in vacuo at ambienttemperature for 24 hours gave 1.74 g (0.0026 mole) of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinonedimaleate salt.

EXAMPLE C Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinoneHydrochloride ##STR10##

1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride is prepared as described hereinbelow:

I. Synthesis of 1-Phenylmethyleneamino-3-[4-(dimethylamino)butyl]-2-imidazolidinone

A stirred solution of1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone (prepared asdescribed in Example B, Part II) (7.0 g, 0.0189 mole), dimethylformamide(125 ml), and dimethylamine hydrochloride (6.15 g, 0.075 mole) is heatedon a steam bath. Sodium methoxide (4.05 g, 0.075 mole) is addedportionwise over approximately 2 hours while heating. After addition,heating is continued 2 hours, then the mixture is cooled to ambienttemperature. The mixture is concentrated under reduced pressure to anoily residue. This residue is suspended in saturated NaHCO₃ solution.(300 ml) and extracted with CH₂ Cl₂ (3×100 ml). The CH₂ Cl₂ extract iswashed with H₂ O (2×100 ml), then dried over MgSO₄. The filteredsolution is concentrated under reduced pressure to an oily-liquidresidue, which is triturated in hexane (2×100 ml), decanted, then driedin vacuo, giving 4.6 g (0.016 mole) of1-phenylmethyleneamino-3-[4-(dimethylamino)butyl]-2-imidazolidinone, asa solid.

II. Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinoneHydrochloride

1-Phenylmethyleneamino-3-[4-(dimethylamino)butyl]-2-imidazolidinone asthe solid prepared in Part II above (4.6 g, 0.016 mole) is dissolved in2 N HCl (125 ml). The cloudy solution is immediately extracted withethyl acetate (2×75 ml). The aqueous phase is treated with 5% Pd/C (50%H₂ O) (2 g) and subjected to H₂ on a Parr apparatus at 40 psi at ambienttemperature. After 1 hour additional catalyst (2 g) is added andhydrogenation is resumed. After shaking 15-16 hours, the catalyst isremoved by filtration. The filtrate is concentrated under reducedpressure to an oily residue, which is azeotroped with acetone (1×25 ml).

The above residue, dimethylformamide (100 ml) and5-(4-chlorophenyl)-2-furanylcarboxaldehyde (prepared as described inU.S. Pat. No. 4,882,354 to Huang et al., assigned to Norwich EatonPharmaceuticals, Inc., issued Nov. 21, 1989, see Example 3, cols. 7, 8,hereby incorporated by reference herein) (3.30 g, 0.0160 mole) arestirred at ambient temperature for several days. The resulting solutionis concentrated under reduced pressure to an oily residue. This residueis dissolved in H₂ O (200 ml), then extracted with ethyl acetate (3×100ml). The aqueous phase is made basic with saturated NaHCO₃ solution.This hazy solution is extracted with ethyl acetate (4×100 ml), and theorganic extract is dried over MgSO₄. The filtered solution isconcentrated under reduced pressure to a solid residue. This residue isrecrystallized from ethyl acetate/hexane. The collected solid isair-dried, dissolved in absolute ethanol (50 ml) and treated withEtOH/HCl until acidic. After cooling several hours the solid iscollected, air-dried, and dried in vacuo at 100°°C. for 2 hours to give1.92 g (0.0045 mole) of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride.

EXAMPLE D Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[2-(dimethylamino)ethyl]-1-imidazolidinoneHydrochloride ##STR11##

The above compound is prepared as described herein.

I. Synthesis of Dimethylaminoethyl Chloride

A stirred solution of dimethylaminoethyl chloride hydrochloride (36.73g, 0.26 mole) in water (65 ml) is chilled on an ice bath. The coldreaction mixture is treated dropwise (15 minutes) with a solution ofsodium hydroxide (10.6 g, 0.26 mole) in water (90 ml) at such a rate asto maintain a reaction temperature of 10° C. Stirring of the reactionsolution is continued for another 15 minutes, and then extraction isconducted with 3×150 ml portions of ether. The extracts are combined anddried over anhydrous MgSO₄. The extract mixture is filtered and thefiltrate concentrated under reduced pressure to leave a clear oil asdimethylaminoethyl chloride (18.2 g).

II. Synthesis of 1-Phenylmethyleneamino-3-[2-(dimethylamino)ethyl]-2-imidazolidinone

A solution of 1-phenylmethyleneamino-2-imidazolidinone (prepared asdescribed in Part II of Example A (14.4 g, 0.076 mole) in drydimethylformamide (338 ml) is stirred and treated portionwise over a 3minute period with sodium hydride (60% dispersion in mineral oil) (3.0g, 0.023 mole). During the addition, a nitrogen sweep is maintained.After the addition is complete, the reaction is heated on a steam bathfor 15 minutes and then chilled to ambient temperature. The nitrogensweep is discontinued and the reaction mixture is treated all at oncewith dimethylaminoethyl chloride (17.66 g, 0.16 mole),prepared asdescribed in Part I herein. The reaction is stirred at ambienttemperature for 15 minutes and then heated at 80° to 90° C. for 3 hours.The reaction is filtered hot, and the filtrate is chilled andconcentrated under reduced pressure to leave an oily residue. Theresidue is treated with 300 ml of water and extracted with 3×300 mlportions of chloroform. The extracts are combined and dried overanhydrous MgSO₄. The extract is filtered and the filtrate isconcentrated under reduced pressure to leave a tan-colored semi-solid.The semi-solid is triturated with anhydrous ether to give the1-phenylmethyleneamino-3-[2-(dimethylamino)ethyl]-2-imidazolidinone,weighing 6.17 g.

III. Synthesis of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[2-(dimethylamino)ethyl]-2-imidazolidinoneHydrochloride

A mixture of 1-phenylmethyleneamino-3-[2-(dimethylamino)ethyl]-2-imidazolidinone, prepared as described in Part II above (6.17g, 0.023 mole) in 2 N HCl (166 ml) is treated with 5% palladium oncarbon (50% wet catalyst) (1.3 g). The reaction mixture is reduced onParr apparatus under hydrogen. The hydrogen uptake stopped after 1/2hour with 100% of theoretical uptake observed. The catalyst is removedand the filtrate concentrated under reduced pressure to leave a whiteresidue. The residue is treated with a solution of5-(4-chlorophenyl)-2-furancarboxaldehyde (prepared as described in U.S.Pat. No. 4,882,354 to Huang et al., assigned to Norwich EatonPharmaceuticals, Inc., issued Nov. 21, 1989, see Example 3, cols. 7, 8,hereby incorporated by reference herein) (4.81 g, 0.023 mole) in drydimethylformamide (137 ml). The reaction is stirred at ambienttemperature overnight. The reaction mixture is filtered and washed withanhydrous ether to give1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[2-(dimethylamino)ethyl]-2-imidazolidinone hydrochloride.

EXAMPLE E Preparation of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinoneHydrochloride Oral Tablet

An oral tablet containing1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[(3-dimethylamino)propyl)]-2-imidazolidinonehydrochloride, (prepared as described in Example A herein), is has thefollowing composition.

    ______________________________________                                        ACTIVE INGREDIENT                                                             1-[[[5-(4-Chlorophenyl)-2-                                                                       350 mg                                                     furanl]methylene]amino]-3-                                                    [3-(dimethylamino)propyl]-2-                                                  imidazolidinone hydrochloride                                                 EXCIPIENTS                                                                    Lactose            197 mg                                                     Sodium Starch Glycolate                                                                          50 mg                                                      Pregelatinized Starch                                                                            30 mg                                                      Talc               12 mg                                                      Magnesium Stearate  6 mg                                                      ______________________________________                                    

Ten thousand tablets having the above composition are prepared asdescribed below:

3.50 kg of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinonehydrochloride; 1.92 kg of lactose, 0.50 kg of sodium starch glycolate,and 0.30 kg of pregelatinized starch are blended in the Patterson-Kellyblender and then granulated with water using the intensifier bar.

The granulation is next dried on trays in an oven or in a fluid beddryer.

The granulation is milled through a 12-mesh screen using an oscillatoror other suitable mill.

The granulation is blended with 120 g of talc and 60 g of magnesiumstearate.

The talc magnesium and granulation mixture is compressed into 440 mgtablets on a suitable tablet machine.

The tablet prepared as described above are given to a patient sufferingfrom cardiac arrhythmia and/or cardiac fibrillation in a suitable dosageregimen.

EXAMPLE F Preparation of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinoneHydrochloride Oral Tablet

An oral tablet containing1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride (prepared as described in Example C herein), has thefollowing composition:

    ______________________________________                                        ACTIVE INGREDIENT                                                             1-[[[5-(4-Chlorophenyl)-2-                                                                        300 mg                                                    furanl]methylene]amino]-3-                                                    [4-(dimethylamino)butyl]-2-                                                   imidazolidinone hydrochloride                                                 EXCIPIENTS                                                                    Dibasic Calcium Phosphate                                                                         219 mg                                                    Crospovidone         60 mg                                                    Povidone             12 mg                                                    Talc                 6 mg                                                     Magnesium Stearate   3 mg                                                     ______________________________________                                    

Ten thousand tablets having the above composition are prepared asdescribed below:

3.00 kg of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]mino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride, 219 kg of dibasic calcium phosphate, 0.60 kg ofcrospovidone, and 0.12 kg of povidone are blended in a Patterson-Kellyblender and then granulated with water using the intensifier bar.

The granulation is dried on trays in an oven or in a fluid bed dryer.The granulation is next milled through a 12 mesh screen using anoscillator or other suitable mill.

The granulation is blended with 60 g of talc and 30 g of magnesiumstearate. Finally, the granulation, talc, and magnesium stearate mixtureis compressed into 600 mg tablets on a suitable tablet machine.

A patient suffering from cardiac arrhythmia and/or cardiac fibrillationis given the tablet, prepared as described above, in a suitable dosageregimen.

EXAMPLE G Preparation of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinoneHydrochloride Oral Capsule

An oral capsule containing1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride, (prepared as described in Example C herein) has thefollowing composition:

    ______________________________________                                        ACTIVE INGREDIENT                                                             1-[[[5-(4-Chlorophenyl)-2-                                                                         300    mg                                                furanl]methylene]amino]-3-                                                    [4-(dimethylamino)butyl]-2-                                                   imidazolidinone hydrochloride                                                 EXCIPIENTS                                                                    Lactose              92     mg                                                Sodium Starch Glycolate                                                                            40     mg                                                Pregelatinized Starch                                                                              25     mg                                                Talc                 12     mg                                                Magnesium Stearate   3      mg                                                Hard Gelatin Capsule Shell                                                                         1      per capsule                                       ______________________________________                                    

Ten thousand oral capsules having the above composition are prepared asdescribed below:

3.00 kg of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride, 0.92 kg of lactose, 0.40 kg of sodium starch glycolate,and 0.25 kg of pregelatinized starch are blended in a Patterson-Kellyblender and granulated with water using the intensified bar.

The granulation is dried on trays in an oven or in a fluid bed dryer.

The granulation is milled through a 12-mesh screen using an oscillatoror other suitable mill. The granulation is blended with 120 g of talcand 30 g of magnesium stearate.

Finally, 472 mg of granulation, talc, and magnesium stearate mixture isfilled into each capsule shell on a suitable capsule filling machine.

A patient suffering from cardiac arrhythmia and/or cardiac fibrillationis given the oral capsule, prepared as described above, in a suitabledosage regimen.

EXAMPLE H Preparation of1-[[[5-[4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinoneHydrochloride Oral Capsule

An oral capsule containing1-[[[5-[4-chlorophenyl)-2-furanyl]methylene]amino]-3-[(3-dimethylamino)propyl]-2-imidazolidinonehydrochloride (prepared as described in Example A herein), has thefollowing composition:

    ______________________________________                                        ACTIVE INGREDIENT                                                             1-[[[5-(4-Chlorophenyl)-2-                                                                         175    mg                                                furanl]methylene]amino]-3-                                                    [3-(dimethylamino)propyl]-2-                                                  imidazolidinone hydrochloride                                                 EXCIPIENTS                                                                    Microcrystalline Cellulose                                                                         110    mg                                                Crospovidone         25     mg                                                Povidone             5      mg                                                Talc                 5      mg                                                Magnesium Stearate   2      mg                                                Hard Gelatin Capsule Shell                                                                         1      per capsule                                       ______________________________________                                    

Ten thousand capsules having the above composition are prepared asdescribed below:

1.75 kg of 1-[[[5-(4-chlorophenyl)-2-furanyl]methyleneamino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone hydrochloride, 1.10kg of microcrystalline cellulose, 0.25 kg of crospovidone, and 0.05 kgof povidone are blended in a Patterson-Kelly or other suitable blenderand then granulated with water using the intensifier bar.

The granulation is dried on trays in an oven or a fluid bed dryer. Thegranulation is milled through a 12 mesh screen using an oscillator orother suitable mill. The granulation is blended with 50 g of talc and 20g of magnesium stearate.

322 mg of the granulation, talc, and magnesium stearate mixture isfilled into each capsule shell on a suitable capsule filling machine.

The oral capsule prepared as described above is given to a patientsuffering from cardiac arrhythmia and/or cardiac fibrillation in asuitable dosage regimen.

EXAMPLE I Preparation of1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinoneHydrochloride Lyophilized Injection

A solution suitable for use as an intravenous (I.V.) injectionconsisting of1-[[[5-(4-chlorophenyl)-2-furanyl]-methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride, (prepared as described in Example C herein), has thefollowing composition:

    ______________________________________                                        ACTIVE INGREDIENT                                                             1-[[[5-(4-Chlorophenyl)-2-                                                                        400 mg                                                    furanl]methylene]amino]-3-                                                    [4-(dimethylamino)butyl]-2-                                                   imidazolidinone hydrochloride                                                 EXCIPIENTS                                                                    Mannitol            500 mg                                                    Citric Acid/Sodium Citate                                                     quantity sufficient to                                                                            adjust pH to 5.5-6.5                                      ______________________________________                                    

The method to make 1,000 vials of the above solution for I.V. injectionis as described hereinbelow.

400 g of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride, 500 g mannitol, and sufficient sodium citrate and/orcitric acid to make a pH solution are dissolved in 10.0 liters ofsterile water for injection.

The resulting solution is aseptically filtered through a 0.2 micronfilter and filled into vials in the amount of 10 ml per vial.

The vials are loaded into a lyophilizer, frozen, dried and stoppered.The lyophilized product is diluted with 10 ml of sterile waterimmediately prior to injection.

A patient suffering from cardiac arrhythmia and/or cardiac fibrillationis given an injection, prepared as described above, in a suitable dosageregimen.

EXAMPLE J

Any of the compounds prepared in Examples A-D herein can be substitutedas the active ingredient in any of the dosage forms prepared in ExamplesE-I herein.

EXAMPLE K

A 57-year-old white male is found unconscious and without palpable pulseat home. A family member initiates cardiopulmonary resuscitation. Thefirst rhythm documented by the rescue squad is ventricular fibrillation.The patient is successfully resuscitated.

The patient had had a myocardial infarction three years ago, and has hadstable angina since.

During the ensuing hospitalization, the patient is found not to have hada myocardial infarction. Monomorphic sustained ventriculartachyarrhythmia is induced by programmed electrical stimulation.

The patient's cardiologist prescribes1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinonehydrochloride at an oral dose of 350 mg, twice a day, after meals. Afterfour days of therapy, the arrhythmia is not inducible at a repeatprogrammed electrical stimulation study. The patient has no furtherepisodes of cardiac arrest over the next 2 years, and treatmentcontinues.

EXAMPLE L

A 65-year-old black male has a syncopal spell preceded by sensations ofpalpitations. Over the preceding several months, the patient hadexperienced frequent palpitations, once with a near-fainting spell. Hehas a history of hypertensive cardiovascular disease, diabetes, remotemyocardial infarction, and obesity.

Sustained monomorphic ventricular tachycardia is induced by programmedelectrical stimulation. The patient's cardiologist prescribes1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[[4-dimethylamino)butyl]-2-imidazolidinonehydrochloride, orally, at a dose of 350, once a day, with a meal. Afterseveral days of therapy, the arrhythmia is noninducible on repeatprogrammed electrical stimulation. There are no further episodes ofsyncope or presyncope over the next three years of observation.

EXAMPLE M

A 58-year-old female Oriental patient with a cardiomyopathy presentswith recurrent syncope. Her ejection fraction is 35%. Programmedelectrical stimulation (PES) induces poorly tolerated sustainedventricular tachyarrhythmia unresponsive to three differentantiarrhythmic drugs. A fourth drug, moricizine, reduces the rate of thetachyarrhythmia and is continued, but the tachyarrhythmia still induceshypotension. She undergoes implantation of an automatic implantablecardioverter-defibrillator (AICD).

The defibrillator discharges twice in the year after implantation of theAICD. The device's monitor records sustained ventricular tachyarrhythmiaat the times of defibrillation. After the second discharge, the patientis hospitalized. Sustained monomorphic ventricular tachyarrhythmia isinduced at PES. Moricizine is discontinued and1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinonehydrochloride at an oral dose of 350 mg, twice a day, after meals, isstarted by the patient's cardiologist.

At repeat PES several days later, the arrhythmia is not inducible andthe defibrillation threshold is unchanged. Over the subsequent year ofobservation, no further discharges are experienced.

EXAMPLE N

A 35-year-old female presents with a 15-year history of frequent(2/month) spells of rapid heartbeat, lasting several hours, associatedwith dizziness and fatigue. These spells cause her to miss time fromwork.

A transtelephonic event monitor demonstrates paroxysmal supraventriculartachycardia. The patient's physician prescribes1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinonehydrochloride at a dose of 175 mg, once a day, after a meal.

Over the subsequent year of observation, the frequency of these spellsdecreases to one every other month, with marked improvement in herattendance record at work.

EXAMPLE O

A 75-year-old male who has a fifty pack-year history of smoking hasknown episodes of atrial fibrillation documented by transtelephonicmonitoring, at the rate of three per month, while on therapy withdigoxin and quinidine. These spells sometimes last over eight hours andprevent the patient's pursuit of his normal daily activities, such asgardening, due to weakness.

The patient's physician switches the patient from quinidine to1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinonehydrochloride orally at a dose of 175 mg, once a day, after a meal. Thefrequency of spells decreases to one a month over the subsequent fourmonths of observation.

EXAMPLE P

A 40-year-old Caucasian male has a several year history of frequentpalpitations. The patient experiences anxiety and shortness of breath atthe time of the palpitations, and has become preoccupied by a fear ofdeath. Extensive evaluations have demonstrated an absence of structuralheart disease. Holter monitoring has shown 2500 PVCs per day, unifocal,with 50 couplets per day. Neither reassurance, nor subsequent therapywith propranolol, have been effective.

The physician prescribes1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinyl)-butyl]-2-imidazolidinonedimaleate at an oral dose of 350 mg, once a day, after a meal.

The frequency of the palpitations decreases and the associated anxietyand shortness of breath are relieved. Holter monitoring now shows 250PVCs per day and no repetitive forms. The preoccupation with deathresolves over several months. The patient is monitored closely, andcontinues to do well over the subsequent five years.

EXAMPLE O

A fifty-eight-year old black male with a ten year history of non-insulindependent diabetes mellitus and a cholesterol level exceeding 300 mg/dlhas a myocardial infarction. Two weeks after the infarction, he isasymptomatic with the exception of dyspnea on exertion. His ejectionfraction is 29%, and 24 hour Holter monitoring reveals 50 unifocal PVCsper hour, occasional couplets, and one five beat run of ventriculartachyarrhythmia. His cardiologist prescribes1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinonehydrochloride at an oral dose of 300 mg after meals. Repeat Holtermonitoring shows abolition of all repetitive forms and an average of 9PVCs per hour. The patient does well over the next three years of followup.

EXAMPLE R

Any of the dosage forms prepared as described in Examples E-I herein,utilizing any of the active ingredients prepared in Examples A-O herein,may be used to treat the individuals described in Examples K-Q herein,in a suitable dosage regimen.

What is claimed is:
 1. A cyclic urea compound which has the structure:##STR12## wherein a) X is a saturated or unsaturated, substituted orunsubstituted 6-membered carbocycle;b) R is a covalent bond; c) Y is asaturated or unsaturated, substituted or unsubstituted 5-memberedheterocycle, wherein said heterocycle has one or two heteroatomsselected from O, S or N; d) R₁, R₂, and R₃ are substituents on the Xmoiety and are independently selected from the group consisting of H,Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃, SO₂, NH, COOH, alkoxy,alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, amino alkyl,acylamino, and acyloxy; e) L is a linking moiety and is selected fromthe group consisting of alkylamino, alkenylamino, alkylimino,alkenylimino, and acylamino, wherein the carbon-containing end of L isbound, through R, at X; and wherein the nitrogen atom of L is bound tothe nitrogen atom at the 3-position of the cyclic urethane ring moiety;f) R₄ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkylacyl, and heteroalkyl; g) A is a substituted or unsubstituted;saturated or unsaturated, straight-chain or branched C₁ -C₈ heteroalkyl;or a substituted or unsubstituted, saturated or unsaturated, heterocyclehaving 5-, 6- or 7-members and one or two heteroatoms selected from O, Nor S; and heteroalkyl A and heterocycle A have at least one nitrogenatom, which nitrogen atom is adjacent to R_(4;) and h) R₅ is asubstituted or unsubstituted C₂ alkyl;and thepharmaceutically-acceptable salts and esters thereof.
 2. A compoundaccording to claim 1 wherein X is unsubstituted and R₁, R₂, and R₃ arehydrogen.
 3. A compound according to claim 1 wherein R₁, R₂, and R₃ areindependently selected from the group consisting of H, Cl, F, Br, CH₃,and OH.
 4. A compound according to claim 1 wherein Y is a 5-memberedheterocycle.
 5. A compound according to claim 1 wherein R is adjacent toX at the 1-position of X, and to Y at the 5-position of Y.
 6. A compoundaccording to claim 5 wherein Y is connected to the carbon-containing endof L at the 2-position of Y.
 7. A compound according to claim 1 whereina heteroatom of Y is oxygen at the 1-position of said heterocycle.
 8. Acompound according to claim 1 wherein one of R₁, R₂, or R₃ is Cl, F, orBr and two of R₁, R₂ or R₃ are H.
 9. A compound selected from the groupconsisting of1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(3-dimethylaminopropyl)tetrahydro-2-(1H)pyrimidinoneand the pharmaceutically acceptable hydrochloride and maleate saltsthereof.
 10. A compound according to claim 1 wherein X is substitutedwith two or more substituents selected from the group consisting of Cl,OH, methoxy, methyl, and benzoyl.
 11. A compound according to claim 1wherein L is selected from the group consisting of alkylimino,alkylamino, and alkenylimino.
 12. A compound according to claim 1wherein R₄ is a C₃ -C₆ alkyl.
 13. A compound according to claim 1wherein R₄ is a substituted alkyl.
 14. A compound according to claim 1wherein A is a heteroalkyl.
 15. A pharmaceutical composition iscomprised of a safe and effective amount of from 15 to 90% of a cyclicurea compound of claim 1, or mixtures thereof, and from 10 to 85%pharmaceutically-acceptable excipients.
 16. A pharmaceutical compositionaccording to claim 15, wherein the pharmaceutically-acceptableexcipients are selected from the group consisting of polymers, resins,plasticizers, fillers, binders, lubricants, glidants, disintegrants,solvents, co-solvents, buffer systems, surfactants, preservatives,sweetening agents, flavoring agents, pharmaceutical grade dyes orpigments, and viscosity agents.
 17. A pharmaceutical compositionaccording to claim 16 comprised of from 15-95% of the cyclic urea activeingredient; 0-2% flavoring agents; 0-50% co-solvents; 0-5% buffersystem; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5%viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15%disintegrants; and 1-10% binders.
 18. A method of treatment for humansor other mammals afflicted with cardiac arrhythmias and/or cardiacfibrillation comprised of administering to said human or other mammal asafe and effective amount of the pharmaceutical composition of claim 15.19. A cyclic urea compound having the general structure: ##STR13##wherein a) R₁, R₂, and R₃ are independently selected from the groupconsisting of H, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH,alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acyloxy and acylamino;b) R₄ is selected from a group consisting of analkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl; c) A is asubstituted or unsubstituted, saturated or unsaturated, straight-chainor branched C₁ -C₈ heteroalkyl or a substituted or unsubstituted,saturated or unsaturated heterocycle having 5-, 6-, or 7-members;wherein said heterocycle has one or more heteroatoms selected fromnitrogen, sulfur, or oxygen; and d) R₅ is a substituted or unsubstitutedC₂ alkyl;and the pharmaceutically-acceptable salts and esters thereof.20. A cyclic urea compound having the following structure: ##STR14##wherein a) the "X-R-Y" portion of the structure is selected from thegroup consisting of 2-acetoxy-5-chlorophenyl;3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl; 2-thienyl;4-pyrimidinyl; 5-methoxycarbonyl-2-furanyl; cyclohexyl;5-chloro-2-hydroxyphenyl; 5-chloro-2-methoxyphenyl;2-methanesulfonylaminophenyl; 3-aminophenyl; 2-methoxyphenyl;5-ethyl-2-furanyl; 3-methoxyphenyl; 2-aminophenyl; 2-furanyl;3,5-dimethyl-4-hydroxyphenyl; 5-acetyloxymethyl-2-furanyl;5-(4-carboxyphenyl)-2-furanyl; 5-(4-methanesulfonylphenyl)-2-furanyl;5-(3,4-dimethoxyphenyl)-2-furanyl;5-(4-methanesulfonylaminophenyl)-2-furanyl;5-(4-bromophenyl)-2-oxazolyl; 5-(4-methoxyphenyl)-2-furanyl;5-(1-cyclohexen-1-yl)-2-furanyl; 5-cyclohexyl-2-furanyl;5-(3-trifluoromethylphenyl)-2-furanyl; 5-(4-methylphenyl)-2-furanyl;2-(4-chlorophenyl)-3-furanyl; 5-(4-chlorophenyl)-2-furanyl;5-(4-fluorophenyl)-2-furanyl; 2-benzyloxy-5-chlorophenyl;4-benzyloxyphenyl; 3-(4-t-butylphenyloxy)phenyl;3-benzoyl-2,4-dichlorophenyl; 2-chloro-3-benzyloxyphenyl;3-(4-chlorophenoxyl) phenyl; 1H-indol-3-yl; 2-fluorenyl; 2-naphthyl;2-hydroxy-1-naphthyl; 2-quinolinyl; and 5-chloro-2-benzofuranyl;b) L isa linking moiety and is selected from the group consisting ofalkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino;wherein the nitrogen atom thereof is bound to the nitrogen atom at the1-position of the cyclic urea ring moiety; c) R₄ is selected from thegroup consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl; d) Ais selected from the group consisting of dimethylamino; diethylamino;bis-2-hydroxy-ethylamino; bis-[(1-methylethyl]amino;N-benzyl-N-methylamino; N-(2-hydroxyethyl)-N-methylamino;N-[(1-methyl)ethyl]--N-[2-hydroxy-2-[(4-methanesulfonyl-amino)phenyl]ethyl]amino;4-phenyl-1-piperazinyl; 4(-2-hydroxyethyl)-1-piperazinyl; 4-[(2-methyl)propyl]-1-piperazinyl; 4-[(2-methyl)propyl]-1-piperazinyl;4-hexyl-1-piperazinyl; 4-benzyl-1-piprazinyl; 1-piperazinyl;4-hydroxy-1-piprazinyl; 1-piperazxinyl; 4-hydroxy-1-piperidinyl;4-methyl-1-piperazinyl; 4-n-butyl-1-piperazinyl; 4-ethyl-1-piperazinyl,3-(4-methyl)-1-piperazinyl)-3-oxopropyl; 4-phenyl-1-piperazinyl;N-(2-pyridinyl)-1-piperazinyl; N-(2-pyrimidinyl)-1-piperazinyl;4-(4-methoxyphenyl)-1-piperazinyl; 4-acetyl-1-piperazinyl;4-methyl-N-phenylamino; 1-imidazolyl,; 4-(2-methylpehnyl)-1-piperazinyl;4-(4-methanesulfonylamino phenyl)-1-9-erazinyl; N-morpholinyl;N-thiomorpholinyl; 4-oxo-1-piperidinyl;2-(t-butoxycarbonyl)-1-pyrrdidinyl; pyrrolidinyl;4-4-acetylphenyl)-1-piperazinyl; hexahydro-1H-azepin-1-yl; and e) R₅ isa substituted or unsubstituted C₂ alkyl.
 21. A cyclic urea compoundhaving the following structure: ##STR15## a) wherein the "X-R-Y" portionof the structure is selected from one of the following: ##STR16## b) Lis a linking moiety and is selected from the group consisting ofalkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino;wherein the nitrogen atom thereof is bound to the nitrogen atom at the1-position of the cyclic urea ring moiety;c) wherein R₄ is selected fromthe group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl; d)wherein the A portion of the structure is selected from one of thefollowing: ##STR17## and the pharmaceutically acceptable salts andesters thereof; and e) R₅ is a substituted or unsubstituted C₂ alkyl.22. A method of treatment for humans or other mammals afflicted withcardiac arrhythmias and/or cardiac fibrillation comprised ofadministering to said human or other mammal a pharmaceutical compositioncomprising from 15 to 90% of a cyclic urea compound according to claim5, pharmaceutically-acceptable salt and esters thereof, or mixturesthereof.
 23. A method of treatment for humans or other mammals afflictedwith cardiac arrhythmias and/or cardiac fibrillation comprised ofadministering to said human or other mammal a pharmaceutical compositioncomprising from 15 to 90% of a cyclic urea compound according to claim8, pharmaceutically-acceptable salt and esters thereof, or mixturesthereof.
 24. A method of treatment for humans or other mammals afflictedwith cardiac arrhythmias and/or cardiac fibrillation comprised ofadministering to said human or other mammal a pharmaceutical compositioncomprising from 15 to 90% of a cyclic urea compound according to claim11, pharmaceutically-acceptable salt and esters thereof, or mixturesthereof.
 25. A pharmaceutical composition for the treatment of cardiacarrhythmia or cardiac fibrillation comprised of from 15 to 90% of acyclic urea compound of claim 1, or any mixtures thereof, and from 10 to85% pharmaceutically-acceptable excipients.
 26. A cyclic urea compoundaccording to claim 1 having the structure: ##STR18## wherein a) X is asaturated or unsaturated, substituted or unsubstituted phenyl;b) R is acovalent bond; c) Y is a furanyl; d) R₁, R₂, and R₃ are substituents onthe X moiety and are independently selected from the group consisting ofH, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃, SO₂, NH, COOH, alkoxy,alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, amino alkyl,acylamino, and acyloxy; e) L is a linking moiety and is selected fromthe group consisting of alkylamino, alkenylamino, alkylimino,alkenylimino, and acylamino, wherein the carbon-containing end of L isbound, through R, at X; and wherein the nitrogen atom of L is bound tothe nitrogen atom at the 3-position of the cyclic urethane ring moiety;f) R₄ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkylacyl, and heteroalkyl; g) A is a substituted or unsubstituted;saturated or unsaturated, straight-chain or branched C₁ -C₈ heteroalkyl;or a substituted or unsubstituted, saturated or unsaturated, heterocyclehaving 5-, 6- or 7-members and one or two heteroatoms selected from O, Nor S; and heteroalkyl A and heterocycle A have at least one nitrogenatom, which nitrogen atom is adjacent to R₄ ; and h) R₅ is a substitutedor unsubstituted C₂ alkyl;and the pharmaceutically-acceptable salts andesters thereof.
 27. A pharmaceutical composition for the treatment ofcardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90%of a cyclic urea compound of claim 25, or any mixtures thereof, and from10 to 85% pharmaceutically-acceptable excipients.
 28. A cyclic ureacompound having the following structure: ##STR19## wherein a) X isphenyl, pyridinyl, thienyl, pyrimidinyl, furanyl, cyclohexyl, oxazolyl,naphthyl, and quinolinyl;b) R is nil or a covalent bond; c) Y is phenyl,pyridinyl, thienyl, pyrimidinyl, furanyl, cyclohexyl, oxazolyl,naphthyl, and quinolinyl; d) R₁, R₂, and R₃ are substituents on the Xmoiety and are independently selected from the group consisting of H,Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃, SO₂, NH, COOH, alkoxy,alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acylamino, and acyloxy; e) L is a linking moiety and is selected fromthe group consisting of alkylamino, alkenylamino, alkenylimino,alkylimino, and acylamino, wherein the nitrogen atom thereof is bound tothe nitrogen atom at the 1-position of the cyclic urea ring moiety; f)R₄ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkyl, alkylacyl, and heteroalkyl; g) A is a substituted orunsubstituted; saturated or unsaturated, straight-chain or branched C₁-C₈ heteroalkyl; or a substituted or unsubstituted, saturated orunsaturated, heterocycle having 6- or 7-members and one or twoheteroatoms selected from N or S; and may not have an oxygen atom; andheteroalkyl A and heterocycle A has at least one nitrogen atom, and saidnitrogen atom is adjacent to R_(4;) and h) R₅ is a substituted orunsubstituted C₂ alkyl;and the pharmaceutically-acceptable salts andesters thereof.
 29. A pharmaceutical composition for the treatment ofcardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90%of a cyclic urea compound of claim 28, or any mixtures thereof, and from10 to 85% pharmaceutically-acceptable excipients.
 30. A cyclic ureacompound according to claim 1 having the following structure: ##STR20##wherein a) R₁, R₂, and R₃ are independently selected from the groupconsisting of H, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH,alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acyloxy, and acylamino;b) L is a linking moiety and is selected from thegroup consisting of alkylamino, alkenylamino, alkenylimino, alkylimino,and acylamino; wherein the carbon-containing end of L is bound to theX-R-Y ring system at Y; and wherein the nitrogen atom of L is bound tothe nitrogen atom at the 3-position of the cyclic urethane ring moiety;c) R₄ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkylacyl, and heteroalkyl; d) A is selected from the group consistingof dimethylamino; diethylamino; bis-2-hydroxy-ethylamino;bis-[(1-methy)ethyl]amino; N-benzyl-N-methylamino;N-(2-hydroxyethyl)-N-methylamino;N-[(1-methyl)ethyl]--N-[2-hydroxy-2-[(4-methanesulfonyl-amino)phenyl]ethyl]amino;4-phenyl-1-piperazinyl; 4(-2-hydroxyethyl)-1-piperazinyl; 4-[(2-methyl)propyl]-1-piperazinyl; 4-[(2-methyl)propyl]-1-piperazinyl;4-hexyl-1-piperazinyl; 4-benzyl-1-piprazinyl; 1-piperazinyl;4-hydroxy-1-piprazinyl; 1-piperazxinyl; 4-hydroxy-1-piperidinyl;4-methyl-1-piperazinyl; 4-n-butyl-1-piperazinyl; 4-ethyl-1-piperazinyl,3-(4-methyl)-1-piperazinyl)-3-oxopropyl; 4-phenyl-1-piperazinyl;N-(2-pyridinyl)-1-piperazinyl; N-(2-pyrimidinyl)-1-piperazinyl;4-(4-methoxyphenyl)-1-piperazinyl; 4-acetyl-1-piperazinyl;4-methyl-N-phenylamino; 1-imidazolyl,; 4-(2-methylphenyl)-1-piperazinyl;4-(4-methanesulfonylamino phenyl)-1-9-erazinyl; N-morpholinyl;N-thiomorpholinyl; 4-oxo-1-piperidinyl;2-(t-butoxycarbonyl)-1-pyridinyl; pyrrolidinyl;4-4-acetylphenyl)-1-piperazinyl; hexahydro-1H-azepin-1-yl; e) R₅ is asubstituted or unsubstituted C₂ alkyl;and thepharmaceutically-acceptable salts and esters thereof.
 31. Apharmaceutical composition for the treatment of cardiac arrhythmia orcardiac fibrillation comprised of from 15 to 90% of a cyclic ureacompound of claim 30, or any mixtures thereof, and from 10 to 85%pharmaceutically-acceptable excipients.
 32. A cyclic urea compoundaccording to claim 1 having the following structure: ##STR21## whereina) R₁, R₂, and R₃ are independently selected from the group consistingof H, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH, alkoxy,alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy,and acylamino;b) R₄ is selected from the group consisting of alkyl,alkenyl, alkynyl, alkylacyl, and heteroalkyl; c) A is selected from thegroup consisting of dimethylamino; diethylamino;bis-2-hydroxy-ethylamino; bis-[(1-methy)ethyl]amino;N-benzyl-N-methylamino; N-(2-hydroxyethyl)-N-methylamino;N-[(1-methyl)ethyl]--N-[2-hydroxy-2-[(4-methanesulfonyl-amino)phenyl]ethyl]amino;4-phenyl-1-piperazinyl; 4(-2-hydroxyethyl)-1-piperazinyl; 4-[(2-methyl)propyl]-1-piperazinyl; 4-[(2-methyl)propyl]-1-piperazinyl;4-hexyl-1-piperazinyl; 4-benzyl-1-piprazinyl; 1-piperazinyl;4-hydroxy-1-piprazinyl; 1-piperazxinyl; 4-hydroxy-1-piperidinyl;4-methyl-1-piperazinyl; 4-n-butyl-1-piperazinyl; 4-ethyl- -piperazinyl,3-(4-methyl)-1-piperazinyl)-3-oxopropyl; 4-phenyl-1-piperazinyl;N-(2-pyridinyl)-1-piperazinyl; N-(2-pyrimidinyl)-1-piperazinyl;4-(4-methoxyphenyl)-1-piperazinyl; 4-acetyl-1-piperazinyl;4-methyl-N-phenylamino; 1-imidazolyl,; 4-(2-methylphenyl)-1-piperazinyl;4-(4-methanesulfonylamino phenyl)-1-9-erazinyl; N-morpholinyl;N-thiomorpholinyl; 4-oxo-1-piperidinyl;2-(t-butoxycarbonyl)-1-pyridinyl; pyrrolidinyl;4-4-acetylphenyl)-1-piperazinyl; hexahydro-1H-azepin-1-yl. d) R₅ is asubstituted or unsubstituted C₂ alkyl;and thepharmaceutically-acceptable salts and esters thereof.
 33. Apharmaceutical composition for the treatment of cardiac arrhythmia orcardiac fibrillation comprised of from 15 to 90% of a cyclic ureacompound of claim 32, or any mixtures thereof, and from 10 to 85%pharmaceutically-acceptable excipients.
 34. A cyclic urea compoundhaving the following structure: ##STR22## wherein a) wherein the "X-R-Y"portion of the structure is selected from one of the following:##STR23## b) wherein R₁, R₂, and R₃ are independently selected from thegroup consisting of H, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH,alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acyloxy, and acylamino;c) L is a linking moiety and is selected from thegroup consisting alkylamino, alkenylamino, alkenylimino, alkylimino, andacylamino; wherein the nitrogen atom thereof is bound to the nitrogenatom at the 1-position of the cyclic urea ring moiety; d) wherein R₄ isselected from the group consisting of alkenyl, alkynyl, alkylacyl, andheteroalkyl; e) R₅ is a substituted or unsubstituted C₂ alkyl; and f)wherein the A portion of the structure is selected from one of thefollowing: ##STR24## and the pharmaceutically-acceptable salts andesters thereof.
 35. A pharmaceutical composition for the treatment ofcardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90%of a cyclic urea compound of claim 34, or any mixtures thereof, and from10 to 85% pharmaceutically-acceptable excipients.
 36. A cyclic ureacompound having the following structure: ##STR25## a) wherein the"X-R-Y" portion of the structure is selected from one of the following:##STR26## b) wherein R₁, R₂, and R₃ are independently selected from thegroup consisting of H, Cl, F, Br, NH₂, CF₃, OH, SO₃ H, CH₃ SO₂ NH, COOH,alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,acyloxy, and acylamino;c) wherein R₄ is selected from the groupconsisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl; d) R₅ is asubstituted or unsubstituted C₂ alkyl; and e) wherein the A portion ofthe structure is selected from one of the following: ##STR27## and thepharmaceutically-acceptable salts and esters thereof.
 37. Apharmaceutical composition for the treatment of cardiac arrhythmia orcardiac fibrillation comprised of from 15 to 90% of a cyclic ureacompound of claim 36, or any mixtures thereof, and from 10 to 85%pharmaceutically-acceptable excipients.